Cystic fibrosis (CF) lung disease features persistent neutrophil accumulation to the airways from the time of infancy (1). In the absence of detectable infection or endotoxin, bronchioalveolar lavage studies have recovered neutrophils ranging from 105 to 107 per mL from the airways of CF children (1-3). These children are frequently exposed to environmental strains of P. aeruginosa, but early infections can be transient, or be eradicated by aggressive antibiotic treatment and an exuberant host defense (4-6). Initial success in eradicating P. aeruginosa acquired from environmental sources likely occurs due to a low density of organisms, a lack of antibiotic resistance, and a generally nonmucoid phenotype. Eventually, persistent P. aeruginosa infection appears inevitable and, by adulthood, 80% of CF patients are chronically infected.
Factors that allow P. aeruginosa to become persistent are of particular interest, as chronic P. aeruginosa infection is associated with increased morbidity and mortality in CF patients (7-9). The persistent P. aeruginosa infection is associated with numerous phenotypic and genetic changes by the bacteria within the CF airway, including the formation of biofilms (10-14). Bacterial biofilms are surface-attached communities of cells encased within a self-produced extracellular polysaccharide matrix independent of, but related to, mucoidy. Biofilm development proceeds through a series of programmed steps including initial surface attachment, formation of three-dimensional microcolonies, and finally the development of a ‘mature’ biofilm (15). The detection of a specific pattern of quorum-sensing signaling molecules in the CF airway suggests that P. aeruginosa in the CF airway exists primarily in the biofilm form (14), a conclusion supported by the inability of antibiotics and host defense mechanisms to eradicate the infection (10, 13, 14).
One of the predominant features of the CF airway is the chronic high-level influx of immune cells. Persistent neutrophil accumulation and necrosis in the CF airways results in sputum highly enriched with DNA, actin, and granule proteins, which are all implicated in the pathogenesis of CF lung disease (1, 16-20). A primary problem of Pseudomonas infection of the cystic fibrosis airway is the longevity of the infection. This infection, which can span decades, persists due to the formation of biofilms, a process facilitated by the presence of neutrophils and neutrophil-derived DNA and F-actin (22).
In addition to CF, a variety of other medical conditions and treatments can cause the undesirable development of biofilms. For example, a variety of microbial infections can be characterized by biofilm formation, including, but not limited to, infectious kidney stones, cystitis, catheter-related infection (kidney, vascular, peritoneal), medical device-related infections, prostatitis, dental caries, chronic otitis media, bronchiectasis, bacterial endocarditis, Legionnaire's disease, orthopedic implant infection, osteomyelitis, wounds, acne, and biliary stents. Therefore, there is a need in the art for improved therapeutic approaches for the inhibition of biofilm formation and/or the reduction or elimination of biofilms, which will be useful for the treatment of conditions such as cystic fibrosis, as well as other diseases and conditions that are associated with the formation of microbial biofilms.